Specificity in NSCLC Treatment Grows With Acceptance of NGS and cfDNA

Angelica Welch

Published: Wednesday, Nov 21, 2018

Benjamin P. Levy, MD

The introduction of next-generation sequencing (NGS) platforms and cell-free DNA (cfDNA) have provided the opportunity for clinicians to be more specific in targeting mutations in patients with non–small cell lung cancer (NSCLC), according to Benjamin P. Levy, MD.

"Adenocarcinoma now can be parsed out into molecular subsets, and based on the molecular subsets identified, they can be wed to a targeted therapy," Levy said. "The story of molecular profiling began with EGFR and ALK, but that is the tip of the iceberg. We now have other actionable mutations, like ROS1 and BRAF, that have approved therapies."

In addition, there are patients with NSCLC who express MET exon 14 alterations, as well as those who express HER2, RET, and NTRK abnormalities. This list of targets answers the question of why genomic testing should be done in patients with NSCLC, according to Levy. This goes beyond lung cancer, he added, as basket trials such as ASCO’s TAPUR study and the NCI-MATCH trial include patients from multiple tumor types.

Questions on Implementing Sequencing

A recently published study in JAMA on advanced NSCLC sought to determine the association of broad-based genomic sequencing and survival in the community oncology setting.1 This study looked at the difference between patients who had comprehensive genomic profiling of their lung cancer versus those who had only had EGFR and ALK panel testing. This retrospective analysis of over 5000 patients showed no difference in outcomes, and broad-based genomic sequencing only directly informed treatment in a minority of patients. This was a surprising result, Levy explained.

Levy advised that clinicians read the study and decipher the meaning for themselves, but consider that this is not necessarily real-world data. He added that there is a deeper clinical value in getting information from a broad-based genomic sequencing assay than just survival.

Community practices are often worried about the cost of doing these broad-based genomic sequencing assays. In a study presented at the 2018 ASCO Annual Meeting, the economic impact of NGS compared with sequential single-gene testing modalities to detect genomic alterations in patients with metastatic NSCLC was analyzed using a decision analytic model.2 This model included 1 million hypothetical newly diagnosed patients with Medicare and commercial health plans.

Findings showed that that NGS could save Center for Medicare and Medicaid Services (CMS) payers $1.4 million to $2.1 million, and commercial insurance providers more than $250,000.

"NGS was cost effective when compared with sequential, exclusionary, and a hotspot panel, both for a CMS and Medicare perspective, and for commercial payers. This is a hypothetical patient population, but there is a lot more work we need to do to understand whether this is cost effective or not," summarized Levy.

Liquid Biopsies

Although NGS is a beneficial option, Levy noted that the turnaround time is often long. There are also issues with tissue procurement. Traditional tissue biopsies are invasive, and there are questions regarding tissue stewardship. Additionally, every institution has a different way of reporting results from the tissue biopsy, Levy said.

"Where does the tissue go? You do the biopsy, it is sent to the pathology lab, then it goes to a whole different bunch of labs," Levy explained. "How do we find the tissue? Where is it? Once it is pinned down, how do you report it? There are challenges with tissue, even in the best of circumstances."

cfDNA is captured by a simple noninvasive blood test, often referred to as a liquid biopsy. Shedding of cfDNA is a product of apoptosis and necrosis, and now more sensitive diagnostic platforms have the capability to genetically interrogate isolate DNA from the blood, explained Levy. This method may circumvent the need for tissue biopsies, he added.

The FLAURA trial of osimertinib (Tagrisso) established the agent as the new standard of care for patients with NSCLC who have EGFR sensitizing mutations. Investigators on this trial showed that there was a concordance between plasma and tumor tissue testing by EGFR mutation status. High sensitivity was observed for those with exon 19 deletions and exon 21 L858R substitution mutations, noted Levy.